Our application Ser. No. 191,470 was broadly concerned with including diuresis and treating hyperaldosteronism by the administration of certain substituted phenyl-2-imino-2-imidazolin-4-ones and substituted phenyl-2-imino-3-substituted-4-imidazolidinones. The latter compounds can also be named as imidazolidines. It has now been found that some of the imidazolidines disclosed in our previous application possess undesirable properties which render them unsuitable for the intended purpose of this invention and such compounds have been excluded herefrom. Such compounds has been excluded on the basis of toxicity, such as death of the animals, crystallization in the urine, lesions in the kidney, great variability in diuretic activity and in effect on Na/K ratio, and failure to obtain an increase in diuretic activity and in Na/K ratio with increased dosage. For example, it has been found that the compound 1-(p-chlorophenyl)-2-amino-4-oxo-2-imidazoline, although active, is too toxic for use in that it causes crystalluria, as a result of its insolubility, and renal tissue damage in test animals. The compound 1-(3,4-dichlorophenyl)-2-amino-4-oxo-2-imidazoline has also been shown to be too toxic for use, in that it is lethal to animals, is toxic to blood cells, and causes crystalluria as well as congestion in the medulla of the kidney. The compounds 1-phenyl-2-imino-3-ethyl-4-oxoimidazolidine, 1-(p-chlorophenyl)-3-ethyl-2-imino-4-oxoimidazolidine and 1-(3,4-dichlorophenyl)-3-ethyl-2-imino-4-oxoimidazolidine, all disclosed in our application Ser. No. 191,470, although active, exhibit one or more undesirable properties which render them unsuitable for the use intended herein.
It has been shown that isomers of the compounds of the present invention, wherein the methyl group is merely moved from one nitrogen to another, are inactive for the purpose of this invention. Such inactive isomers are 1-phenyl-2-methylamino-4-oxo-2-imidazoline and 1-p-chlorophenyl-2-methylamino-4-oxo-2-imidazoline. It has also been shown that compounds are inactive or otherwise unsuitable for the purposes of this invention when the substituent on the 3-position of the imidazolidine ring is other than a methyl or ethyl group. For example, compounds such as 1-p-chlorophenyl-2-imino-3-n-propyl-4-oxoimidazolidine, 1-phenyl-2-imino-3-n-propyl-4-oxoimidazolidine, and 1-p-chlorophenyl-2-imino-3-n-butyl-4-oxoimidazolidine have been shown to be inactive.
It has now been found that only a limited number of tetrasubstituted imidazolidines and the pharmaceutically acceptable salts thereof demonstrate sufficient diuretic effect or antialdosteronic activity when administered to animals, and are sufficiently non-toxic and otherwise desirable to warrant consideration for the purpose of this invention.
Certain 1-phenyl-2-imino-3-alkyl-4-oxoimidazolidines are disclosed, as glycocyamidines, in U.S. Pat. No. 2,557,911 and J. Am. Chem. Soc. 73: 2942 (1951). U.S. Pat. No. 2,557,911, at column 4, lines 9-14 discloses that such imidazolidines are useful only as chemotherapeutic agents, bactericides and catalysts. There is no disclosure in this patent of their utility as diuretic agents or their use in the treatment of hyperaldosteronism. This type of diuretic action could not have been part of the utility in the patent above since the mineralocorticoid hormone, aldosterone, was not discovered until 1953 and the ability to antagonize its action and thereby produces a diuretic effect was not discovered until 1955. Moreover, at the time of the patent, a chemotherapeutic agent meant that such agent had to do with the treatment of infectious disease. The closest specific compound to those of this invention disclosed in the above patent is the compound 1-phenyl-3-ethylglycocyamidine or, by our nomenclature, 1-phenyl-2-imino-3-ethyl-4-oxoimidazolidine. This imidazolidine is not encompassed within the present invention. Tests have shown that 1-phenyl-2-imino-3-ethyl-4-oxoimidazolidine as well as 1-(p-chlorophenyl)-2-imino-3-ethyl-4-oxoimidazolidine, although active for the purpose of this invention, do not give a useful increase in diuretic activity and in Na/K ratio with increased dosage, are variable in their activity and are otherwise unsuitable for the purposes of this invention. Tests have also shown that the higher alkyl compounds disclosed in U.S. Pat. No. 2,557,911, such as the specifically disclosed 1-phenyl-3-n-octyl-glycocyamidine (or 2-imino-4-oxoimidazolidine) and the broadly disclosed 1-phenyl-2-imino-3-n-propyl-4-oxoimidazolidine, 1-(p-chlorophenyl)-2-imino-3-n-propyl-4-oxoimidazolidine, and 1-(p-chlorophenyl)-2-imino-3-n-butyl-4-oxoimidazolidine, are inactive and therefore unsuitable for the purposes of this invention. A nitro-substituted compound is disclosed in the above references but such compounds, including also 1-(p-nitrophenyl)-2-imino-3-methyl-4-oxoimidazolidine, are inactive for the purposes of this invention, as also are a variety of other substituted-phenyl compounds. The scope of U.S. Pat. No. 2,557,911 comprises six categories of compounds: (1) 1-alkylglycocyamidines; (2) 1-arylglycocyamidines; (3) 1,3-dialkylglycocyamidines; (4) 1,3-diarylglycocyamidines; (5) 1-alkyl-3-arylglycocyamidines; and (6) 1-aryl-3-alkylglycocyamidines. In addition to the categories shown above to be inactive, those of category 1 such as the specifically disclosed 1-n-octylglycocyamidine and of category 4 such as the specifically disclosed 1,3-diphenylglycocyamidine and 1-phenyl-3-(p-nitrophenyl)glycocyamidine are also inactive for the purpose of this invention. As mentioned above, two compounds of category 2 were active but too toxic for use; the rest of the compounds tested were inactive. Therefore, only compounds of category 6 are the subject of the present invention and, furthermore, only a very small part, namely two compounds, of those comprising category 6 are within the scope of the present invention.